N-(haloalkyl)-endo-perhydro-4, 7-methanoisoindoles



United States Patent 3,118,905 N-(HALOALKYL)-ENDO-PERHYDRO-4fl- METHANQISOINDULES James W. Bolger, Canoga Park, Calif., assignor to Biker Laboratories, line, Northridge, Calit, a corporation of Delaware No Drawing. Filed July 27, 1962, Ser. No. 213,050 7 Claims. (Cl. 26tl319) This invention relates to compositions of matter classitied in the art of chemistry as substituted isoindoles.

The invention sought to be patented resides in the concept of a chemical compound in which there is attached to the nitrogen atom of an endo-perhydro-4,7-methanoisoindole nucleus of its hereinafter disclosed equivalents, a halodcwer alkyl group.

As used throughout the specification and in the claims the terms lower alkyl and lower alkylene embrace straight and branched chain alkyl and alkylene radicals, respectively, containing 1 to 6 carbon atoms and the term halo denotes the halogens fluorine, chlorine, bromine and iodine.

The tangible embodiments of this invention possess the inherent general physical chart-acteristi'cs of being, in the form of their acid addition salts, white crystalline solids. Spectral data reveal no unsatunation except as present in the benzene ring of the equivalent 7a-phenyl substituted compound. These aforementioned physical characteristics, taken together with the nature of the starting materials and mode of synthesis, positively confirm the structure of the compounds sought to be patented.

lThe tangible embodiments of this invention possess the inherent applied use characteristics of having pharmacological activity as anti-hypertensive agents and as agents for prolonging the effects of pharmacologioally active barbituric acid derivatives as determined by recognized and accepted pharmacological test procedures, and, in addition, are valuable chemical intermediates in the preparation of other substituted indoles having significant pharmacological activity. For example, treatment of these compounds with an alkali metal cyanide yields the pharmacologically active N-cy-ano-lower-alkyl-endo-perhydro-4,7-methanoisoindoles which are described and claimed in my application entitled N-Cyanoalkyl-Endo- Perhydro-4,7-Methan-oisoindoles, filed concurrently herewith.

The manner and process of making and using the invention will now be generally described so as to enable a person skilled in the art of chemistry to make and use the same as follows:

The starting materials for the compounds of this invention, N-hydroxy-lower-alkyl-endo-perhydro-4,7-methanoisoindoles and their 7a-substituted equivalents, are prepared according to the method described in my application entitled Canboxylio Acid Esters of Endo-Perhydro- 4,7-Methanoisoindoles and Intermediates, Serial No. 213,051, filed July 27, 1962.

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2 The preparation of the tangible embodiments .of this invention is illustrated as follows:

where A is lower alkylene, R is hydrogen or its hereinafter disclosed equivalent and X is halogen.

Starting materials bearing at the 7a-position a lower alkyl or phenyl group, or such groups bearing one or more substituents such as lower alkoxy, halogen, trifluoromethyl, or lower alkyl in the case of phenyl, are the full equivalent of the N-hydroxy-lower-alkyl-endo-perhydro-4,7-methanoisoindole, starting materials in the foregoing reaction sequence, thereby to produce 7a-substituted N-halo-lower-alkyl finished products which have the same utility as N-halo-lower-alkyl-endo-perhydro-4,7- methanoisoindoles.

The reaction depicted herein-above is carried out by treating the starting material with a thionyl halide, such as thionyl chloride or thionyl bromide or with hot hydroh ali c acid such as hydrochloric or hydrobomic acid in the presence of an inert solvent such as methylene chloride, benzene and the like.

The tangible embodiments of this invention can, if desired, be converted into their non-toxic pharmaceutically acceptable acid addition and quaternary ammonium salts by conventional procedures. Typical acid addition salts include the hydocloride, hydrobromide, citrate, maleate, sulfate, nitrate and the like. Typical quaternary ammonium salts are those formed With such alkyl halides as methyl iodide, ethyl bromide, n-hexyl bromide and the like. Such salts are the full equivalent of the free bases and are included within the scope of this invention.

The tangible embodiments of this invention, either as the free base or in the form of a non-toxic pharmaceutically acceptable acid addition or quaternary ammonium salt, may be combined with conventional pharmaceutical diluents and carriers, to form such dosage forms as tablets, capsules, solutions, suspensions, suppositories and the like.

The best modecontemplated by the inventor of carrying out this invention will now be set forth as follows:

EXAMPLE 1 N -(2 -Clzlroetlzyl) -Endo-Perlzydro4,7-Methanoisoindolc H ydroclzloride N-( 2-hydroxyethyl)-endo-perhydro-4,7 methanoisoindole (43 g., 0.238 mole) is dissolved in 200 ml. of methylene chloride. Thionyl chloride (42.5 g, 0.356 mole) is added dropwise at room temperature. The solution is stirred for 2.5 hours. Upon addition of ether (-500 ml.), a solid is obtained. The crude solid is dissolved in methylene chloride, treated with Norit A and ether is added to induce crystallization. Yield: 49 g. (87%) of white crystals, M.P. 243-2 44 C.

AnaIysis.--Calculated for C H NC1 C, 55.93%; H, 8.11%. Found: C, 55.85%; H, 8.13%.

The following examples illustrate the preparation of other tangible embodiments of this invention.

EXAMPLE 2 N (2 -Clzl0roezlzyl -7a-Methyl-Endo-Perhy tire-4,7- M etlzanoisoindole Hydrochloride N- (Zhydroxye thyl -7a-methyl-endo-perhydro-4,7-methanoisoindole (100 g., 0.513 mole) is dissolved in 400 ml. of methylene chloride. Thionyl chloride (91 g., 0.77 mole) is added dropwise. The initially exothermic reaction mixture is then stirred at room temperature for two hours. Anhydrous ether is added to crystallize the product. The white solid is washed several times with anhydrous ether to remove excess thionyl chloride. The crude white product is recrystallized from ethanol/ ether (anhydrous). Yield: 99 g. (77%) of white crystals, M.P. 258 C. (d.).

Analysis.Calculated for C H NCl C, 57.61%; H, 8.46%; N, 5.60%. Found: C, 57.77%; H, 8.55%; N, 5.44%.

EXAMPLE 3 N -(2 -Cl; loropropyl -Endo-Perhydro-4,7-Metlzanoisoindole Hydrochloride N- 2hydroxypropyl -endo-perhydro4,7-methan0isoindole (39 g., 0.173 mole) is dissolved in 200 ml. of methylene chloride. Thionyl chloride (19 ml., 0.24 mole) is added dropwise. The resulting solution is stirred at room temperature for two hours. Anhydrous ether is added to crystallize the product. After washing the crude product several times with anhydrous ether to remove the excess thionyl chloride, the product is recrystallized from ethanol-ether (anhydrous). Yield: 22.5 g. (52%), M.P. 228229 C.

Analysis.Calculated for C H NCl z C, 57.61%; H, 8.46%; Cl, 28.34%. Found: C, 58.04%; H, 8.04%; CI; 27.09%.

EXAMPLE 4 N-(2 '-ClzIoro-1 '-Metlzylethyl) -Endo-Perlzydro4,7- Methanoisoindole Hydrochloride N-(2'-hydr0Xy-1-methylethyl) endo perhydro 4,7- methanoisoindole (15 g., 0.065 mole) is dissolved in 150 ml. of methylene chloride. Thionyl chloride (7.5 ml., 0.101 mole) is added dropwise. The solution is then stirred at room temperature for two hours. The solvent is removed by distillation leaving an oily residue. The oil solidifies after washing with several portions of an- 4 hydrous ether. The crude product is recrystallized from ethanol/ether (anhydrous). Yield: 14.5 'g. of white crystals, M.P. 219-220 C.

Analysis.Calculated for C H NCl C, 57.61%; H, 8.46%; C1, 28.34%. Found: C, 57.83%; H, 8.55%; Cl, 28.59%.

EXAMPLE 5 N-(2'-ClzIoroet/zyl)-7a-P/zenyl-Endo-Perlzydro-l,7- M ethanoisoindole Hydrochloride N-(2'-hydroxyethyl)-7a-phenyl endo perhydro 4,7- methanoisondole (15 g., 0.051 mole) is dissolved in ml. of methylene chloride. Thionyl chloride (6 ml., 0.088 mole) is slowly added. The reaction mixture is then stirred at room temperature for two hours. The solvent is removed by distillation leaving a clear oily residue. The oil crystallizes after being washed with anhydrous ether. The crude product is recrystallized from ethanol/ ether (anhydrous). Yield: 12..7 g. (80%) of white crystals, M.P. 187-189 C.

Analysis.Calculatec1 for C H NCl C, 65.39%; H, 7.42%; C1, 22.71%. Found: C, 65.46; H, 7.33%; CI, 22.90%.

EXAMPLE 6 N-(3'-Chloropr0pyl )-End0-Perl1ya'ro4,7-Methanoisoindole Hydrochloride N-(3-hydroxypropyl)-endo-perhydro lfi-methanoisoindole (133.0 g., 0.576 mole) is dissolved in 250 ml. of methylene chloride. Thionyl chloride (73.0 g., 0.613 mole) is slowly added. The reaction mixture is stirred at room temperature for two hours. The solvent is removed by distillation leaving an oily residue. The oil solidifies after washing with several portions of anhydrous ether. The crude product is recrystallized from ethanol/ ether (anhydrous). Yield: 121.0 g. of white crystals, M.P. 246-247 C.

Analysis.-Calculated for C H NCI C, 57.6%; H, 8.4%; Cl, 28.4%. Found: C, 57.49%; H, 8.14%; Cl, 28.13%.

The subject matter which the applicant regards as his invention is particularly pointed out and distinctly claimed as follows.

I claim:

1. A compound of the formula No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N05 3,1 18 9o5 January 21 1964 James W, Bo lger I It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column l, line l5 for "of" read or column 2 line 49 for "hydocloride" read hydrochloride column 4 line 58 for "-chloroethylread chloroethy1) same line 58 for "prehydro" read perhydro =0 Signed and sealed this 23rd day of June 1964 SEAL Aittest:

ERNEST W. SWIDER EDWARD J. BRENNER Commissioner of Patents Attesting Officer 

1. A COMPOUND OF THE FORMULA 